Abstract  Supplementary materials

Abstract  Acetylene, C2H2, is a highly reactive, commercially important hydrocarbon. Its reactivity is related to its triple bond between carbon atoms and, as a consequence, its high positive free energy of formation. Because of its explosive nature, long distance shipping or pressurized storage is not recommended. Thus acetylene is generally used as it is produced without shipping or storage. Commercially, acetylene is used primarily as a raw material for the synthesis of a variety of organic chemicals. In the United States, this accounts for ∼90% of acetylene usage, with the balance being used for metal welding and cutting. Worldwide acetylene production peaked in the mid-1960s, after which it declined dramatically as processes were developed to substitute lower cost olefins and paraffins for the acetylene feedstock. 1,4-Butanediol production accounts for 90% of the demand for acetylene for chemical production. Although acetylene production in Japan, China, and Eastern Europe is still based on the calcium carbide process, the large producers in the United States, Western Europe, and Russia now rely principally on the partial oxidation of natural gas. However, much of the incremental growth in production is based on producing acetylene as a coproduct of ethylene in the steam cracking process. As a coproduct, acetylene is much less costly than as produced from partial oxidation or calcium carbide.

Abstract  The penetration of ibuprofen and flurbiprofen, non-steroidal anti-inflammatory agents, was investigated from drug films deposited by acetone evaporation on cadaver skin in an open cell 'in-vivo mimic' design. Increased dosage did not produce a proportional increase in the permeation and maximizing the skin-drug contact did not increase penetration: both factors indicate that absorption from deposited drug films was dissolution rate-limited. Occlusion of the skin did not increase the dissolution rate of the deposited drug film, but did elevate the penetration of drug already present within the skin at the time of occlusion. The diffusion coefficients for both drugs were calculated by two methods, yielding 1.8 +/- 1.3 X 10(-11) cm2 s-1 and 1.0 +/- 0.56 X 10(-11) cm2 s-1 for ibuprofen and 1.9 +/- 0.59 X 10(-11) cm2 s-1 and 0.77 +/- 0.23 X 10(-11) cm2 s-1 for flurbiprofen. Increasing the acetone-skin contact time from 2 min to 2 h did not significantly alter the permeability of the skin. Absorption of flurbiprofen was similar from 10 and 100% saturated aqueous solutions, suggesting that the skin has a limited capacity for flurbiprofen transport beyond which further increase in drug penetration may be difficult. N-Methyl-2-pyrrolidone enhanced the penetration flux of ibuprofen sixteenfold and flurbiprofen, over threefold. The 'in-vivo mimic' design for permeation experiments has thus proved to be useful for evaluating the kinetics of topical therapy and the mechanism of action of potential penetration enhancers.

Abstract  At relatively low concentrations (less than 3M) the aprotic solvents: dimethylsulfoxide, N-methylpyrrolidone, tetramethylurea and hexamethylphosphoric triamide, inhibited beta-D-galactoside transport by whole cells, and the derived membrane vesicles of Escherichia coli. Inhibition was not due to gross leakiness of the membrane and could be largely reversed by a simple washing procedure...

Abstract  Deoxyphomalone (1), dimethyl 4-methyl-2,6-pyridinedicarboxylate (2), stemphyperylenol (3), and N-methyl-2-pyrrolidone (4) were isolated from the fermentation broth of a strain of the fungus, Alternaria tenuissima. This fungus was isolated from the soil underlying the lichen, Peltigera didactyla, which had been collected from Wapusk National Park in Northern Manitoba. The structures of the compounds were determined by comprehensive analysis of their spectroscopic data including FT-IR, 1D and 2D NMR spectroscopy and mass spectrometry; and their bioactivities were tested against E.coli cells. The taxonomic identity of the fungus was confirmed by ITS sequencing of its ribosomal DNA.

Abstract  OBJECTIVES: The exposure of seven workers and three on-site study examiners to N-methyl-2-pyrrolidone (NMP) was studied in an adhesive bonding compound and glue production facility.

METHODS: Airborne NMP was analysed by personal and stationary sampling on activated charcoal tubes. NMP and its main metabolites, 5-hydroxy-N-methyl-2-pyrrolidone (5-HNMP) and 2-hydroxy-N-methylsuccinimide (2-HMSI), were analysed in pre-shift and post-shift spot urine samples by gas chromatography-mass spectrometry. The workers were examined with respect to irritation of the eyes, the mucous membranes and the skin, and health complaints before and after the work-shift were recorded.

RESULTS: The time-weighted average concentration of NMP in most work areas varied between 0.2 and 3.0 mg/m3. During the manual cleaning of stirring vessels, valves and tools, 8-h TWA exposures of up to 15.5 mg/m3 and single peak exposures of up to 85 mg/m3) were observed. NMP and its metabolites were detected in two pre-shift urine specimens. NMP and 5-HNMP concentrations in post-shift urine samples of five workers and three on-site study examiners were below 125 microg/g creatinine and 15 mg/g creatinine, respectively, while two vessel-cleaning workers showed significantly higher urinary NMP concentrations of 472 and 711 microg/g creatinine and 5-HNMP concentrations of 33.5 and 124 mg/g creatinine. 2-HMSI was detectable in four post-shift samples (range: 1.6-14.7 mg/g creatinine). The vessel cleaner with the highest NMP exposure reported irritation of the eyes, the upper respiratory tract and headaches.

CONCLUSIONS: The results of this study indicate a relatively low overall exposure to NMP in the facility. An increased uptake of NMP occurred only during extensive manual vessel cleaning. Health complaints associated with NMP exposure were recorded in one case and might be related to an excessive dermal exposure due to infrequent and inadequate use of personal protective equipment.

Abstract  N-Methyl-2-pyrrolidone (NMP) is a versatile organic solvent frequently used for surface cleaning such as paint stripping or graffiti removal. Liquid NMP is rapidly absorbed through the skin but dermal vapour phase absorption might also play an important role for the uptake of the solvent. This particular aspect was investigated in an experimental study with 16 volunteers exposed to 80 mg/m(3) NMP for 8 h under either whole-body, i.e. inhalational plus dermal, or dermal-only conditions. Additionally, the influence of moderate physical workload on the uptake of NMP was studied. The urinary concentrations of NMP and its metabolites 5-hydroxy-N-methyl-2-pyrrolidone (5-HNMP) and 2-hydroxy-N-methylsuccinimide (2-HMSI) were followed for 48 h and analysed by gas chromatography-mass spectrometry (GC-MS). Percutaneous uptake delayed the elimination peak times and the apparent biological half-lives of NMP and 5-HNMP. Under resting conditions, dermal-only exposure resulted in the elimination of 71 +/- 8 mg NMP equivalents as compared to 169 +/- 15 mg for whole-body exposure. Moderate workload yielded 79 +/- 8 mg NMP (dermal-only) and 238 +/- 18 mg (whole-body). Thus, dermal absorption from the vapour phase may contribute significantly to the total uptake of NMP, e.g. from workplace atmospheres. As the concentration of airborne NMP does not reflect the body dose, biomonitoring should be carried out for surveillance purposes.

Abstract  The potential toxicity of N-methylpyrrolidone was evaluated following dietary administration for 13 weeks to male and female beagle dogs at dosage levels of 25, 79 and 250 mg per kg body weight per day. Body weight gain and food consumption, hematological and clinical chemical data, and ophthalmic, gross and histopathological examinations were used to study possible toxicological or pathological effects. No statistically significant treatment-related effects that were judged to be biologically meaningful were seen in any parameters of either male or female animals exposed to N-methylpyrrolidone at any dose level. However, a dose-dependent decrease in body weight and increase in platelet count that correlated with increased megakaryocytes was observed. Serum cholesterol in males decreased with increasing doses.

Abstract  The water-miscible co-solvents polyethylene glycol 400 (PEG400), N-methyl-2-pyrrolidone (NMP), and N, N-dimethylacetamide (DMA) exhibit the potential to increase the solubility of poorly water-soluble compounds and therefore they represent promising vehicles for compound delivery using osmotic pumps in early discovery experiments. Thus, the selected co-solvents were investigated for their compatibility with the interior of ALZET osmotic pumps. Moreover, 1-week pumps were filled with mixtures of either the co-solvents with water (60:40, v/v), with neat PEG400, or with PEG400/water mixtures of different concentrations. It was determined whether the composition of an experimental formulation could have an impact on the overall pump rate with 14C-mannitol being used as the model compound. It was found that neat PEG400 was compatible with the reservoir material, whereas NMP and DMA were tolerable only in aqueous solutions up to 60%. PEG400, NMP, and DMA mixtures with water (60:40) resulted in release rates comparable to those of water and PEG400/water mixtures of lower co-solvent concentration. Moreover, as demonstrated using the various PEG400/water mixtures, the amount of co-solvent in the formulation had no significant impact on the overall release profile. By contrast, the use of neat PEG400 resulted in a significant decrease in the pump rate.

Abstract  The use of polymethylmethacrylate (PMMA) to reinforce vertebral bodies (Vertebroplasty) leads to an increase in the Young's modulus of the augmented vertebral body. Fractures in the adjacent vertebrae may be the consequence thereof. Hence, PMMA with a reduced Young's modulus may be suitable for vertebroplasty. The goal of this study was to produce and characterize stiffness-adapted PMMA cements. Modified PMMA bone cements were produced by adding N-methyl-pyrrolidone (NMP). Young's modulus, yield strength, polymerization temperature, setting time, and hardening behavior of different cements were analyzed. Focus was on the mechanical properties of the material after different storage conditions (in air at room temperature and in PBS at 37 degrees C). The Young's modulus decreased from 2670 MPa (air)/2384 MPa (PBS) for the regular cement to 76 MPa (air)/320 MPa (PBS) for a material composition with 60% of the MMA substituted by NMP. Yield strength decreased from 85 MPa (air)/78 MPa (PBS) to 2 MPa (air)/24 MPa (PBS) between the regular cement and the 60% composition. Polymerization temperature decreased from 70 degrees C (regular cement) to 48 degrees C for the 30% composition. The hardening behavior exhibited an extension in handling time up to 200% by the modification presented. Modification of PMMA cement using NMP seems to be a promising method to make the PMMA cement more compliant for the use in cancellous bone augmentation in osteoporotic patients: adjustment of its mechanical properties close to those of cancellous bone, lower polymerization temperature, and extended handling time.

Abstract  The mechanism of the azide-nitrile cycloaddition mediated by different Brønsted and Lewis acids has been addressed through DFT calculations. In all cases activation of the nitrile substrate by the Brønsted or Lewis acid catalyst was found to be responsible for the rate enhancement. According to DFT calculations the cycloaddition proceeds in a stepwise fashion involving the initial formation of an open-chain imidoyl azide intermediate. Kinetic experiments performed using N-methyl-2-pyrrolidone as solvent and sodium azide as azide source demonstrate that all evaluated Brønsted acids have the same efficiency toward cycloaddition with benzonitrile, suggesting that hydrazoic acid is the actual dominant catalytic species in these tetrazole syntheses. Lewis acids such as Zn or Al salts perform in a similar manner, activating the nitrile moiety and leading to an open-chain intermediate that subsequently cyclizes to produce the tetrazole nucleus. The most efficient catalyst evaluated was 5-azido-1-methyl-3,4-dihydro-2H-pyrrolium azide, which can readily be generated in situ from aluminum chloride, sodium azide in N-methyl-2-pyrrolidone. The efficiency of this catalyst has been examined by preparation of a series of 5-substituted-1H-tetrazoles. The desired tetrazole structures were obtained in high yields within 3-10 min employing controlled microwave heating.

Abstract  The aim of this study was to investigate if the uptake of N-methyl-2-pyrrolidone (NMP), a widely used industrial chemical, increases after exposure to NMP in humid air compared to dry air. NMP has been described to be an airway irritant and a developmentally toxic compound. Six male volunteers were exposed to NMP, three at the time, for 8h in an exposure chamber. They were each exposed on four different occasions to air levels of 0 and 20mg NMP/m(3) in dry and humid air. Blood and urine were sampled before, during and up to 5 days after the end of the 8-h exposure. Plasma and urine were analysed for NMP and its metabolites, using liquid chromatography-tandem mass spectrometry. There was no statistically significant increase in the total cumulated excretion of NMP and its metabolites in urine after exposure in humid air as compared to dry air. Furthermore, there were no differences in the levels of peak concentrations in either plasma or urine. Also, no differences were found in AUC between the exposures. However, there were large individual differences, especially for the exposure in humid air. A not previously identified metabolite in human, 2-pyrrolidone (2-P), was identified. The results do not support a significantly higher absorption of NMP at exposure in humid air as compared to dry air. However, the large individual differences support the use of biological monitoring for assessment of NMP exposure. In addition, 2-P was confirmed to be an NMP metabolite in humans. This may be of importance for the developmental toxicity of NMP since 2-P have been described to be a reproductively toxic substance.

Abstract  The kinetics of formation of amide, 4, from the corresponding carboxylic acid by reaction with the isopropyl ester of methionine (MIPE), mediated by carbodiimide EDCI, 1, and HOBt, 2, have been studied in 1-methyl-2-pyrrolidinone (NMP) using reaction calorimetry. The reaction rates have been found to be independent of the concentration of HOBt, showing that the rate-determining step is the reaction between the carboxylic acid and EDCI to give the corresponding O-acylisourea. The pH dependence of the observed rate constants for O-acylisourea formation is consistent with a second-order reaction between doubly protonated EDCI (EDCIH2(2+), 6) and the carboxylate group. The observed rate constants fall sharply at high pH, as the fraction of EDCI as EDCIH2(2+) continues to fall strongly, whereas the carboxylic acid group is already fully ionized. The rate constant, kP, for reaction between the carboxylate group of acid, 3, and EDCIH2(2+) has a value of kP = 4.1 x 10(4) M(-1) s(-1) at 20 degrees C, some 10(5) times higher than similar rate constants measured in water. The subsequent catalytic cycle, involving reaction of O-acylisourea with HOBt to give HOBt ester, which then reacts with the amine to give the amide with regeneration of HOBt, determines the product distribution. In the case of the amino acid, 3, reaction of the O-acylisourea with MIPE to give amide, 4, is increasingly favored at higher pH values over that with the less basic internal aromatic amine of 3 to give the diamide 5.

Abstract  Bone tumours may recur locally even after wide surgical excision and systemic chemotherapy. Local control of growth may be accomplished by the addition of cytostatic drugs such as methotrexate (MTX) to bone cement used to fill the defect after surgery and to stabilise the reconstructive prosthesis. We have studied the elution kinetics of MTX and its solvent N-methyl-pyrrolidone (NMP) from bone cement and their biological activities in five cell lines of osteosarcoma and in osteoblasts, and compared them with the effects of the parent compounds alone and in combination. Our findings show that MTX is released continuously over months at concentrations highly cytotoxic to osteosarcoma cells and suggest that the impregnated bone cement would be effective in the long term. Proliferating osteoblasts, however, were much less sensitive towards MTX. The dose-response relationship for NMP and experiments with MTX/NMP-mixtures show that the eluted concentrations of solvent are not toxic and do not influence the effects of MTX. We suggest that bone cement containing MTX dissolved in NMP releases the drug in a suitable and effective way and may be of value in the treatment of bone tumours.

Abstract  Aggregates of reaction intermediates form during the early stages of aniline oxidative polymerization whenever the initial mole ratio of proton concentration to aniline monomer concentration is low ([H(+)](0)/[An](0) <or= 1.0). Detailed characterization is carried out on those aggregates. The intermediate aggregates show a UV-Vis absorption peak at around 410 nm when dispersed in aqueous solution, whereas the peak is centered on 370 nm when dissolved in an organic solvent such as N-methylpyrrolidone. The electronic band gap decreases when the intermediates aggregate to form a solid, and thus, the absorption peak is red-shifted. Gel permeation chromatography (GPC) shows the aggregates contain a major low molecular weight peak with a long tail. The oligoanilines with low molecular weights consistently show a UV-Vis absorption peak at around 370 nm. Mass spectrometry confirms that the intermediate aggregates contain mainly a component with mass number 363 (M + H(+)), likely a tetramer. UV-Vis, GPC, mass spectrometry, NMR, FTIR, and XRD characterization results are presented and chemical structures for the tetramer are proposed. The major components of the intermediate aggregates are likely highly symmetric phenazine- and dihydrophenazine-containing structures. These particular organic compounds have not been identified before as intermediates. The aggregation and precipitation of the tetramers apparently stabilizes these intermediates. The aggregates are highly crystalline, as evidenced by powder X-ray diffraction. A new reaction mechanism for the formation of these intermediates is proposed.

Abstract  Novel in situ forming implants are presented showing a promising potential to overcome one of the major practical hurdles associated with local periodontitis treatment: limited adhesion to the surrounding tissue, resulting in accidental expulsion of at least parts of the implants from the patients' pockets. This leads to high uncertainties in the systems' residence times at the site of action and in the resulting drug exposure. In the present study, the addition of different types and amounts of plasticizers (acetyltributyl citrate and dibutyl sebacate) as well as of adhesive polymers (e.g., cellulose derivatives such as hydroxypropyl methylcellulose) is shown to allow for a significant increase in the stickiness of poly(lactic-co-glycolic acid)-based implants. The systems are formed in situ from N-methyl pyrrolidone-based liquid formulations. Importantly, at the same time, good plastic deformability of the implants can be provided and desired drug release patterns can be fine-tuned using several formulation tools. The antimicrobial activity of this new type of in situ forming implants, loaded with doxycycline hyclate, was demonstrated using the agar well diffusion method and multiple Streptococcus strains isolated from the oral microflora of patients suffering from periodontitis.

Abstract  Due to low aqueous solubility and slow dissolution rate, spironolactone, a synthetic steroid diuretic, has a low and variable oral bioavailability. Nanoparticles were thus prepared by antisolvent precipitation in this work for accelerating dissolution of this kind of poorly water-soluble drugs. Effects of surfactant type/concentration and feed drug concentration on the precipitated particle size were evaluated. It was found that introduction of spironolactone solution in N-methyl-2-pyrrolidone (NMP) to the antisolvent water can produce the particles in the submicron range with hydroxypropyl methylcellulose (HPMC) as the stabilizer. The particle size decreased with the increase of HPMC concentration from 0 to 0.125% (w/v), further increase of which did not affect the size significantly. Increasing feed drug concentration from 10 to 100 mg/ml resulted in the particle size decrease. In comparison with raw drug, the chemical structure of nanosized spironolactone was not changed but the crystallinity was reduced. Dissolution of spironolactone nanoparticles in 0.1M HCl was 2.59 times faster than raw drugs in 60 min.

Abstract  BACKGROUND AND PURPOSE: To evaluate the ready-to-use iodine-containing polyvinyl alcohol (I-PVA) dissolved in the low angiotoxic solvent N-methyl pyrrolidone (NMP) for embolization of porcine wide-necked aneurysms.

METHODS: Fourteen broad-based carotid sidewall aneurysms were surgically constructed in 7 swine. I-PVA (40%) in NMP was injected under temporary balloon occlusion bridging the aneurysm neck. After 4 weeks, follow-up angiography, multisection CT angiography (MSCTA), and 3T MR imaging including MR angiography (MRA) sequences were performed. Afterward, harvested aneurysms were investigated histopathologically.

RESULTS: The liquid embolic was well visible under fluoroscopy and displayed a favorable precipitation pattern, allowing for controlled polymer delivery. Ten aneurysms (71%) were initially completely occluded, whereas in 1 aneurysm, a minimal polymer leakage was observed. The other 4 aneurysms (29%) were almost completely occluded. One animal suffered a lethal rebleeding from the anastomosis after uneventful embolization. Aneurysms embolized with I-PVA could be discriminated well from the parent artery without beam-hardening artifacts on MSCTA, and no susceptibility artifacts were encountered on MR imaging. Histologic examination revealed all aneurysms covered with a membrane of fibroblasts and an endothelial cell layer while a moderate intraaneurysmal inflammatory response to the polymer was observed.

CONCLUSION: I-PVA dissolved in NMP has proved its effectiveness for the embolization of experimental wide-necked aneurysms. This precipitating liquid embolic offers several interesting features in that it needs no preparation before use and no radiopaque admixtures, the latter allowing for artifact-free evaluation of treated aneurysms with MSCTA and MRA. Moreover, it uses NMP as a solvent, which has only a low angiotoxicity.

Abstract  A method for the synthesis of polymer-bound 7-acylamino-benzodiazepine-2,5-diones is described. The amino group of an alpha-amino acid is linked to polystyrene or TentaGel resin via reductive amination of polymer-bound 4-alkoxy-2,6-dimethoxybenzaldehyde. Acylation with unprotected 5-nitroanthranilic acid is followed by base-catalyzed ring closure. Reduction of the nitro group yields enantiomerically pure 7-aminobenzodiazepin-2,5-dione attached via the N-4 atom to the resin. Acylation of the amino group on the aromatic ring with acid chlorides in N-methylpyrrolidone (no DMF, no base!) followed by cleavage from the resin using TFA/Me(2)S/water (90:5:5) provides the acylated benzodiazepinones in 52-69% (PS resin) and 41-48% (TG resin) yield (based on the theoretical loading) and >70% purity (HPLC, 210 nm). Using Fmoc-protected tyrosine fluoride in NMP gives the amino acid-coupled benzodiazepinones in 24% (PS resin) and 31% (TG resin) yield.

Abstract  The recently reported process of chiral induction in a metal-organic framework (MOF) by nonchiral guest adsorption, demonstrated on the prototypical MOF-5, may revolutionize the production of MOFs for enantioselective separation and catalysis. Herein, we describe an investigation employing multiscale molecular simulation to discover the microscopic mechanism of chiral induction and investigate the stability of the resulting framework. Our results explain how the molecular size and chemical nature of N-methyl-2-pyrrolidone (NMP) give rise to the chiral transformation in MOF-5, whereas it cannot occur for other guest molecules, such as N,N-dimethylformamide (DMF). Moreover, we show that the guest-free CMOF-5 structure is energetically unstable, with either the achiral conventional structure or a closed pore structure preferred, demonstrating that chirality will not be retained upon activation of CMOF-5. While this limits the usability of chiral induction in MOFs, our study opens new avenues for the use of other guest molecules and provides microscopic insight into this unexpected outcome of guest-framework interactions in a soft porous crystal.

Abstract  Novel polylactide (PLA) microspheres endowed with hydrophilic and bioadhesive surfaces as injectable formulations for the controlled release of fenretinide were prepared, using a novel technique based on the co-precipitation of PLA with gelatin, at the interface of a liquid dispersion formed by the addition of N-methylpyrrolidone containing PLA and dextrin (DX), towards an aqueous solution of gelatin (G). The resulting PLA-G-DX microspheres were compared with others prepared by the same technique using polylactide-co-glycolide (PLGA), with or without DX, and with or without phosphatidylcholine. Of the different systems, the PLA-G-DX microspheres had the best morphological, dimensional and functional characteristics. They had the highest drug loading, and their drug release was the most efficient over time without any burst effect. Their in vitro anti-tumoural activity was strongly enhanced with respect to the pure fenretinide. This paralleled the increased drug concentration inside the cells due to their marked bioadhesion to the tumour cell membranes as indicated by scanning electron microscope images.

Abstract  Aramid macroscale fibers, also called Kevlar fibers, exhibit extremely high mechanical performance. Previous studies have demonstrated that bulk aramid macroscale fibers can be effectively split into aramid nanofibers (ANFs) by dissolution in dimethylsulfoxide (DMSO) in the presence of potassium hydroxide (KOH). In this paper, we first introduced the ANFs into the structure of graphene nanosheets through non-covalent functionalization through π-π stacking interactions. Aramid nanofiber-functionalized graphene sheets (ANFGS) were successfully obtained by adding the graphene oxide (GO)/DMSO dispersion into the ANFs/DMSO solution followed by reduction with hydrazine hydrate. The ANFGS, with ANFs absorbed on the surface of the graphene nanosheets, can be easily exfoliated and dispersed in N-methyl-2-pyrrolidone (NMP). Through a combination of these two ultra-strong materials, ANFs and graphene nanosheets (GS), the resultant ANFGS can act as novel nanofillers for polymer reinforcement. We used the ANFGS as an additive for reinforcing the mechanical properties of poly(methyl methacrylate) (PMMA). With a loading of 0.7 wt% of the ANFGS, the tensile strength and Young's modulus of the ANFGS/PMMA composite film approached 63.2 MPa and 3.42 GPa, which are increases of ∼84.5% and ∼70.6%, respectively. The thermal stabilities of ANFGS/PMMA composite films were improved by the addition of ANFGS. Additionally, the transparencies of the ANFGS/PMMA composite films have a degree of UV-shielding due to the ultraviolet light absorption of the ANFs in the ANFGS.